. Ixodes ticks serve as the vector for 3 human infections in the U.S.-- Lyme disease, Babesiosis and human granulocytic ehrlichiosis. The incidence of all three diseases has been increasing over the last decade. Despite the availability of antibiotic therapy after infection, each of these diseases is associated with significant morbidity or, in some cases, even mortality. Preventative measures targeted towards human disease have been largely limited to tick avoidance methods and there are currently no human vaccines available for any of the diseases. An alternative strategy for prevention of human disease would be to develop treatments to reduce carriage and transmission of these pathogens in their wild reservoirs, Ixodes ticks and small rodents such as white-footed mice. Our laboratory has been involved in developing a vaccinia virus (VV) based anti-Borrelia burgdorferi vaccine for white-footed mice based on the outer surface A (OspA) protein of B. burgdorferi. While this strategy has shown promise, protection from an OspA vaccine for mice is limited to Lyme disease. Recent progress by other investigators has shown the potential for the development of anti-tick vaccines. Vaccination of animals with tick antigens has been shown to decrease feeding and infestation by ticks and/or to decrease transmission and acquisition of infectious agents by ticks. In this proposal, we will test tick antigens expressed in a VV vector for their ability to protect against tick infestation and disease transmission when administered orally to mice. Identification of anti-tick targets will allow us to develop a multivalent vaccine containing both tick and pathogen antigens for improved reduction of tick borne diseases in reservoir animals. The overall goal of this project is translational, in that, we will attempt to make use of recent advances in scientific understanding and apply them towards the development of a vaccine that could have a direct impact on the incidence of human, tick transmitted diseases through reduction of disease in wildlife reservoirs. The tick-borne infections, Lyme disease, Ehrlichiosis and Babesiosis, are significant public health problems in the U.S. One potential approach to the control of these diseases is to reduce carriage of the organisms in their wild-life reservoirs. In this proposal, we outline a strategy to develop an ecologically targeted vaccine that blocks transmission of these pathogens between tick and mammalian reservoirs through inhibition of tick feeding, thus reducing human infections by reducing the numbers of infected ticks.